The purpose of this proposal is to adapt a technology that we have developed for monitoring residual disease in leukemia patients to monitor residual autoimmune disease in Celiac Disease patients. Celiac disease has a significant burden on quality of life, as it is one of the most frequent autoimmune diseases, with an estimated prevalence of approximately 1% in populations of European descent. The sole treatment for celiac disease is to adopt a gluten-free diet, which resolves acute symptoms and intestinal pathology in a large majority of patients. Approximately one in twenty celiac patients will develop refractory celiac disease, where intestinal inflammation persists after 12 months of adherence to a gluten free diet. Refractory celiac disease patients are at risk for an aggressive non-Hodgkin lymphoma that is without effective treatments. Refractory celiac disease diagnosis is made from a biopsy of the small intestine, so a non-invasive diagnostic tool that could monitor celiac disease resolution after adopting a gluten-free diet would be very useful to clinicians caring for patients with this disease, allowing for less-costly, more frequent followup of patients than intestinal biopsies. We have developed an innovative technology for the massively parallel sequencing of somatically rearranged T cell receptors, and have successfully applied this technology to monitor minimal residual disease burden in T-cell acute lymphocytic leukemia. This proposal will support platform development extending our technology to monitor residual disease status in celiac patients. In aim 1 we collect pilot data on the utility of our technology in monitoring the expected contraction of high frequency T cell clones in intestinal biopsies, in order to demonstrate that th technology can effectively track an oligoclonal repertoire of autoreactive T cells directly in the affected tissue of celiac patients as the adopt a gluten-free diet. In aim 2 we extend the analysis to peripheral blood draws from the same set of patients, in order to test the sensitivity of our platform for monitoring the enteric TCR repertoire in a non-invasive blood draw. In summary, this proposal proposes to test the feasibility of monitoring CD disease status by tracking the oligoclonal repertoire of enteric T cells. If proven feasible, then tracking these populations of cells could prove useful in the early detection of refractory celiac disease, a precursor for a more serious lymphoma that affects celiac patients. Our methods might allow for cheaper and less-invasive detection of RCD, allowing for earlier detection and more aggressive clinical intervention to prevent lymphoma development. If this application of our assay proves feasible, then similar methods for tracking clonal populations of T cells could prove useful in monitoring disease status in many other T-cell driven autoimmune diseases.